がんの生物学的特性の研究の総括

• Project/Area Number: 06281104
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas (A)
• Allocation Type: Single-year Grants
• Research Institution: Kyushu University (1998-1999); Showa University (1996-1997); The University of Tokyo (1994-1995)
• Principal Investigator: 笹月 健彦 (1998-1999) 九州大学, 生態防御医学研究所, 教授 (50014121); 黒木 登志夫 (1994-1997) 昭和大学, 腫瘍分子生物学研究所, 所長 (90006073)
• Co-Investigator(Kenkyū-buntansha): 渋谷 正史 東京大学, 医科学研究所, 教授 (10107427) ; 黒木 登志夫 昭和大学, 腫瘍分子生物学研究センター, 教授 (90006073) ; 宮園 浩平 癌研究所, 生化学部, 部長 (90209908) ; 高井 義美 大阪大学, 医学部, 教授 (60093514) ; 月田 承一郎 京都大学, 大学院・医学研究科, 教授 (50155347) ; 笹月 健彦 九州大学, 生医研, 教授 (50014121) ; 田原 栄一 広島大学, 医学部, 教授 (00033986) ; 菅村 和夫 東北大学, 医学部, 教授 (20117360)
• Project Period (FY): 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥69,000,000 (Direct Cost: ¥69,000,000); Fiscal Year 1999: ¥10,800,000 (Direct Cost: ¥10,800,000); Fiscal Year 1998: ¥10,000,000 (Direct Cost: ¥10,000,000); Fiscal Year 1997: ¥20,000,000 (Direct Cost: ¥20,000,000); Fiscal Year 1996: ¥20,000,000 (Direct Cost: ¥20,000,000); Fiscal Year 1995: ¥6,000,000 (Direct Cost: ¥6,000,000); Fiscal Year 1994: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: がん / 遺伝子 / 増殖 / 分化 / 細胞死 / 転移 / 細胞間相互作用 / シグナル伝達 / 細胞増殖 / 細胞分化 / がん転移 / ヒトがん / がん遺伝子 / がん細胞 / 細胞生物学 / アボトーシス / アポトーシス

Research Abstract

「がん生物」領域は、がんの基礎研究からヒトがんを材料とする臨床研究まで広い範囲をカバーし、計画研究(1)5班、計画研究(2)28班、公募研究63班の計96班、研究者数229名と総括班より構成された。この特定領域では、がんの生物学的特性を明らかにすることによって、がんの予防、診断、治療に貢献することを目的とする。遺伝子発現の調節、シグナル伝達、細胞の増殖と分化、細胞死、細胞の構造と機能、細胞間相互作用、生体内ホメオスタシス維持機構など、生命科学のもっとも基本的な問題、およびヒトがんの特性、浸潤・転移などのがん固有の問題を、以下のように研究対象として設定し、研究を推進した。
A01. 細胞の増殖・分化・細胞死 A04. 浸潤・転移
A02. 細胞の構造と機能 A05. ヒトがんの特性
A03. 細胞間相互作用
平成11年度は、以下のような活動を行った。
(1)「がん生物」ワークショップ:「がん生物」に属する全ての研究代表者が参加して自由に討議し、研究の一層の進展をはかり、さらに研究資料の交換、共同研究の設定を促進することを目的として、ワークショップを開催した。平成11年度は、「がん特定領域研究(A)代表者会議に連動して、7月12日、研究代表者による研究発表を行った。これを一つの機会として各研究者間の交流、研究協力の実がはかられた。
(2)研究成果の公表
「がん生物」の分野で卓越した研究成果を挙げている研究者を選び、文部省がん重点公開・合同シンポジウムでその成果を発表した。
本年度で、平成6年より開始された「がんの生物学的特性の研究(がん生物)」は、6年間が終了することになったが、「がん生物」で行われてきた研究は卓越しており、来年度より開始される新しい特定領域研究の方向性を与えることとなった。

Research Products

• [Publications] Sirasawa, S. et al.: "Rnx-deficiency results in congenital central hypoventilation"Nature Genet.. (in press).
• [Publications] Okumura, K. et al.: "Activated Ki-Ras suppresses 12-O-tetradecanoylphorbol-13-acetate-induced activation of the c-June NH2-terminal kinase pathway in human colon cancer cells"Cancer Res.. 59. 2445-2450 (1999)
• [Publications] Fujii M. et al.: "Roles of bone morphogenetic protein type I receptors and Sad proteins in osteoblastic and chondroblasti differentiation"Mol. Biol. Cell. 10. 3801-3813 (1999)
• [Publications] Akiyoshi S. et al.: "c-Sky acts as a transcriptional co-repressor in TGF-b signaling through interaction with Smads"J. Biol. Chem.. 274. 35269-35278 (1999)
• [Publications] Kuroki T. et al.: "Adenovirus-mediated gene transfer to keratiocytes -A Review-"J. Invest. Dermatol. Symp. Proc.. 4. 153-157 (1999)
• [Publications] Miyaki M. et al.: "Frequent mutation of beta-catenin and APC genes in primary colorectal tuhors from patients with herediary nonpolyposis colorectal cancer"Cancer Res.. 59. 4506-4509 (1999)
• [Publications] Shibuya M. et al.: "Structure and function of VEGF Receptor-1 and -2"Curr. Topics Microbiol. Immunol.. 237. 59-83 (1999)
• [Publications] Takeda N. et al.: "The BCR-ABL oncoprotein potentially interacts with the xeroderma pigmentosum group B protein"Proc. Natl. Acad. Sci. USA. 96. 203-207 (1999)
• [Publications] Sonoda N. et al.: "Clostridium perfringens enterotoxin fragment removes specific claudins from tight junction strands : Evidence for direct involvement of claudins in tight junction barrier"J. Cell Biol.. 147. 195-204 (1999)
• [Publications] Morita K. et al.: "Endothelial claudin : claudin-5/TMVCF constitutes tight junction strands in endothelial cells"J. Cell Biol.. 147. 185-194 (1999)
• [Publications] Umikawa M. et al.: "Association of frabin with the actin cytoskeleton is essential for microspike formation through activation of Cdc42 small G protein"J. Biol. Chem.. 274. 25197-25200 (1999)
• [Publications] Ikeda W. et al.: "Afadin : a key molecule essential for structral organization of cell-cell junctions of polarized epithelial during embryogenesis"J. Cell Biol.. 146. 1117-1132 (1999)
• [Publications] Ono Y. et al.: "Clinicopathologic significance of laminin-5γ2 chain expressin in squamous cell carcinoma of the tongue : Immunohistochemical analysis of 67 lesions"Cancer. 85. 2315-2321 (1999)
• [Publications] Genda T. et al.: "Cell motility mediated by Rho and Rho-associated protein kinase plays a critical role in intrahepatic metastasis of human hepatocellular carcinoma"Hepatology. .30. 1027-1036 (1999)
• [Publications] Ishino K.: "Phorbol seterinduced G1 arrestin BALB/MK-2 mouse keratinocytes is mediated by d and h isoform of protein kinase." Jpn.J.Cancer Res.(in press). (1999)
• [Publications] Sasazuki T.: "Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an inrelated donor." New Engl.J.Med.339. 1177-1185 (1998)
• [Publications] Okada F.: "Impact of oncogenes in tumor angiogenesis:Mutant K-ras upregulation of VEGF/VPE is necessary,but not sufficient for yumorigenicity of human colorectal carcinoma cells." Proc.Natl.Acad.Sci.USA. 95. 3609-3614 (1998)
• [Publications] Fukui Y.: "Highly restricted T cell repertoire shaped by a single majoy histocompatibility complex-peptide ligand in the presence of a single rearranged cell repertoire β chain." J.Exp.Med.188. 897-907 (1998)
• [Publications] Ohba M.: "Induction of differentiation innormal human keratinocytes by adenovirus-mediated introduction of the h and d'isoforms of protein kinase." Mol.Cell.Biol.18. 5199-5207 (1998)
• [Publications] Hiratsuka S.: "Flt-1 lacking the tyrosine kinase domain is sufficient or normal development and angiogenesis in mice." Proc.Natl.Acad.Sci.USA. 95. 9349-9354 (1998)
• [Publications] Luo JC: "Ifferential inhibition of fluid accumulation and tumor growth in two mouse ascites tumors by an anti-bascular endothelial growth factor/permeablility factor neutralizing antibody." Cancer Res.58. 2594-2600 (1998)
• [Publications] Hirohashi S.: "Actinin-4,a novel actin-bundling protein associated with cell motility and cancer invasion." J.Cell.Biol.140. 1383-1393 (1998)
• [Publications] Hirohashi S.: "Inactivation of the E-chadherin-mediated cell adhesion system in human cancers." Am.J.Pathol.153. 333-339 (1998)
• [Publications] Lu SL.: "Hereditary nonpolyposis colorectal cancer associated with germline mutation in the TGF- type II receptor gene." Nature Genet.19. 17-18 (1998)
• [Publications] Kawabata M.: "Smad proteins exist asmonomers in vivo and undergo homo- and hetero-oligomerization upon activation by serine/threonine kinase recepyors." EMBO J.17. 4056-4065 (1998)
• [Publications] Saitoh M.: "Occludin-deficient embryonic stem cells can differentiate into polarized epithelial cells bearing tight junctions." J.Cell.Biol.141. 397-408 (1998)
• [Publications] Matsui T.: "Pho-kinase phosphorylates carboxy-terminal threonines of EPM proteins and regulates their head-to-tail association." J.Cell.Biol.140. 647-657 (1998)
• [Publications] Miki H.: "Induction of filopodium formation by a WASP-related actin-depolymerizing protein N-WASP." Nature. 391. 93-96 (1998)
• [Publications] Mochida S.: "Role of the Doc2_α-Munc13-1 interaction in the neurotransmitter relaase process." Proc.Natl.Acad.Sci.USA. 95. 11418-11422 (1998)
• [Publications] Kashiwagi,M: "Specific inhibition of hair follicle formation by epidermal growth factor in an organ culture of developing mouse skin." Develop.Biol.189. 22-32 (1997)
• [Publications] Takeshita,T.: "STAM,signal transducing adaptor molecule is associated with Janus kinases and involved in signaling for cell growth and c-myc induction." Immunity. 6. 449-457 (1997)
• [Publications] Takahashi,T.: "The 230kDa mature form of KDR/Flk-1 (VEGF receptor-2) activates the PLCg pathway and partially induces mitotic signals in NIH3T3 fibroblasts." Oncogene. 14. 2079-2089 (1997)
• [Publications] Takaishi,K.: "Regulation of cell-cell adhesion by Rac and Rho small G proteins in MDCK cells." J.Cell Biol.139. 1047-1059 (1997)
• [Publications] Sakakibara,A.: "Possible involvement of phosphorylation of occludin in tight junction formation." J.Cell Biol.137. 1393-1401 (1997)
• [Publications] Kuniyasu,H.: "Growth inhibitory effect of interferon-β is associated with the induction of cyclin-dependent kinase inhibitor p27Kip1 in a human gastric carcinoma cell line." Cell Growth & Differentiation. 8. 47-52 (1997)
• [Publications] Ohmori,M.: "Acitvated Ki-ras enhances sensitivity of ceramide-induced apoptosis without c-Jun NH2-terminal kinase/stress-activated protein kinase or extracellular signal-regulated kinase activation in human colon cancer cells." Cancer Research. 57. 4714-4717 (1997)
• [Publications] Murakami,A.: "Absence of down-requlation and translocation of the isoform of protein kinase C in normal human keratinocyte" J.Invest.Dermatol.106. 790-794 (1996)
• [Publications] Saito,S.: "Expression of the interleukin-2 receptor (IL-2R) chain on cord blood mononuclear cells." Blood. 87. 3344-3350 (1996)
• [Publications] Ozaki,T.: "Rom1p and Rom2p are GDP/GTP echange proteins (GEPs) for the Rholp small GTP-binding protein in Saccharomyces cerevisiae." EMBO J.15. 2196-2207 (1996)
• [Publications] Akagi,M.: "Inhibition of cell growth by transforming growth factor bl is associated with p53-independent induction of p21 gastric coroinoma cells." Jpn.J.Cancer Res.87. 377-384 (1996)
• [Publications] Yamamoto,K.: "Functional interaction between human histocompatibility leukocyte antigen (HLA) class II and mouse CD4 molecule in antigen recognition by T cells in HLA DR and DO transgenie mice." J.Expt.Med.180. 165-171 (1996)
• [Publications] Takeda,H.: "V-src kinase shifts the cadherin-based celladhesion from the strong to the weak state and b-catenin is not requited for the shifts." J.Cell Biol.131. 1839-1847 (1996)
• [Publications] Tagawa,T.: "The cell cycle-dependent nuclear import of v-Jun is regulated by phosphorylation of a serine adjacent to the unclear localization signal" J.Cell Biol.130. 255-263 (1995)
• [Publications] Ohno,K.: "Functional analysis of the human interleukin 2 receptor σ chain gene promoter." J.Biol.Chem.270. 7479-7486 (1995)
• [Publications] Yamamori,B.: "Purification of a Ras-dependent mitogen-activated protein kinase kinase kinase from bovine bovine brain cytosol and its identification as a complex of B-raf and 14-3-3 proteins." Biochem.mol.Biol.270. 11723-11726 (1995)
• [Publications] Tahara,E.: "Genetic alterations in human gastrointestinal cancers." Cancer. 75. 1410-1417 (1995)
• [Publications] Yamamoto,K.: "Functional interaction between human histocompatibility leukocyte antigen (HLA) Class II and mouse CD4 molecule in antigen recognition by T cell in HLA-DR and DO transgenic mice." J.Exp Med.180. 165-177 (1994)
• [Publications] Yonemura,S.: "Cell-to-cell adherens junction formation and actin filament organization:similarities and differences between non-polarized fibroblasts and polarized epithelial cells." J.Cell Sci.108. 127-142 (1995)
• [Publications] Kuroki,T.: "Why are human cells resistant to malignant cell transformation in vitro ?" Jpn.J.Cancer Res.84. 1091-1100 (1993)
• [Publications] Kondo,M.: "Functional participation of the IL-2 receptor γ chain in IL-7 receptor complexes." Science. 263. 1453-1454 (1994)
• [Publications] Nakanishi,H.: "Different functions of smg GDP dissociation stimulator and mammalian counterpartof yeast Cdc25." J.Biol.Chem.269. 15085-15091 (1994)
• [Publications] Ito,R.: "Interleukin 1α acts as an autocrine growth stimulator for human gastric carcinoma cells." Cancer Research. 53. 4102-4106 (1993)
• [Publications] Shirasawa,S.: "Altered growth of human colon cancer cell lines disrupted at activated Ki-ras." Science. 260. 85-88 (1993)
• [Publications] Tsukita,Sa.: "ERM family members as molecular linkers between the cell surface glycoprotein CD44 and actin-based cytoskeletons." J.Cell Biol.126. 391-401 (1994)